PROJECT SUMMARY ? UNIVERSITY OF NORTH CAROLINA-CHAPEL HILL, FROHLICH Sustained attention represents a fundamental dimension of cognitive control and refers to the process of allocating cognitive resources to appropriately respond to infrequent but task-relevant stimuli. Sustained attention differs from the more commonly studied shifting or dividing attention since it lacks the defining features of capacity limitation and competition. Deficits in sustained attention are common in psychiatric illnesses including attention deficit hyperactivity disorder, bipolar disorder, and schizophrenia. Understanding the network substrate of sustained attention will thus significantly advance our ability to develop circuit-based therapeutics that selectively engage and restore the activity patterns that drive sustained attention. Synchronization in two higher-order networks have emerged as neural sub- strate of sustained attention and cognitive control in general. First, the frontoparietal network acts as a generator of top-down control signals. Second, the posterior thalamo-cortical network gates processing of input and exhibits task- modulation during sustained attention. Yet, it remains unclear if the synchronization through oscillations in these two networks plays a causal in sustained attention and more broadly in cognitive control. Targeted brain stimulation of individual network nodes with rhythmically patterned stimulation offers the opportunity to manipulate specific network oscillatory patterns and examine the resulting change in behavioral performance to establish a causal role of the targeted activity pattern. Such causal neuroscience of higher-order brain function will fundamentally advance our understanding of how cognition arises from large-scale electrical activity patterns in the brain. The overall objective is to identify the causal role of oscillatory functional interactions in sustained attention by rhythmic optogenetic stimula- tion. We will employ a widely used paradigm of sustained attention in animals, the five-choice serial reaction time task (5-CSRTT), in combination with rhythmic optogenetic stimulation and multisite electrophysiology in ferrets. We use the ferret (instead of more commonly used rodent species) for the study of the oscillatory substrate of cognitive function since we previously found that the ferret shares two fundamental top-down brain rhythms with humans: frontal theta oscillations that provide control of posterior parietal cortex and posterior alpha oscillations that gate visual perception. The proposed project builds on our published work of oscillatory interactions in these two networks as a function of engagement with both the 5-CSRTT and sensory input in ferrets, and our preliminary data of suc- cessful modulation of neuronal spiking, functional connectivity, and behavioral performance in the 5-CSRTT by fre- quency-specific rhythmic optogenetic stimulation. We hypothesize that oscillatory functional interaction in these two networks is dynamically regulated to drive sustained attention in this task. Completion of these three aims will pro- vide an in-depth understanding of the causal role of frontoparietal and posterior thalamo-cortical network in sustained attention. The rationale of this project is that advancing the causal investigation of synchronization in higher-order brain structures in cognitive control will open new avenues for the development of novel diagnostic and therapeutic strategies for deficits in cognitive control. The proposed work is thus of high translational significance and broad impact since sustained attention is impaired in numerous psychiatric illnesses.